Host defense mechanisms against viruses and virus infected cells consist of highly complex and incompletely understood interactions between cellular and humoral elements. This proposal focuses on interactions of the humoral immune system, primarily complement (C), with human pathogen viruses and with virus infected human cells. C is a major biological mediator in man, able to produce inflammation and to mediate the opsonic, phagocytic, or lytic destruction of certain viruses and virus infected cells. This proposal examines the possibility that C functions as a natural defense mechanism operative against viruses and virus infected cells prior to antibody formation. The interactions of highly purified components of the C system with isolated Epstein-Barr Virus (EBV) and with human cells infected with EBV will be examined. EBV is a candidate human cancer virus as it is oncogenic in subhuman primates, transforms human cells in vitro, causes a human lymphoproliferative disorder, and is strongly associated with two human malignancies. For comparison, interactions of C with another virus, influenza, and with human cells infected with influenza, measles, and an RNA tumor virus (retrovirus) will also be studied. A basic molecular and mechanistic approach will be employed. The emphasis will thus be on the structural features of the virus of infected cell which trigger the C components and on the nature and mechanism of the activation reactions. The biological consequences to the virus and the infected cell of these interactions will be analyzed and the precise manner in which the viruses and virus infected cells are neutralized or destroyed will be determined.